Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

LaTonya J Hickson, Larissa G P Langhi Prata, Shane A Bobart, Tamara K Evans, Nino Giorgadze, Shahrukh K Hashmi, Sandra M Herrmann, Michael D Jensen, Qingyi Jia, Kyra L Jordan, Todd A Kellogg, Sundeep Khosla, Daniel M Koerber, Anthony B Lagnado, Donna K Lawson, Nathan K LeBrasseur, Lilach O Lerman, Kathleen M McDonald, Travis J McKenzie, João F Passos, Robert J Pignolo, Tamar Pirtskhalava, Ishran M Saadiq, Kalli K Schaefer, Stephen C Textor, Stella G Victorelli, Tammie L Volkman, Ailing Xue, Mark A Wentworth, Erin O Wissler Gerdes, Yi Zhu, Tamara Tchkonia, James L Kirkland, LaTonya J Hickson, Larissa G P Langhi Prata, Shane A Bobart, Tamara K Evans, Nino Giorgadze, Shahrukh K Hashmi, Sandra M Herrmann, Michael D Jensen, Qingyi Jia, Kyra L Jordan, Todd A Kellogg, Sundeep Khosla, Daniel M Koerber, Anthony B Lagnado, Donna K Lawson, Nathan K LeBrasseur, Lilach O Lerman, Kathleen M McDonald, Travis J McKenzie, João F Passos, Robert J Pignolo, Tamar Pirtskhalava, Ishran M Saadiq, Kalli K Schaefer, Stephen C Textor, Stella G Victorelli, Tammie L Volkman, Ailing Xue, Mark A Wentworth, Erin O Wissler Gerdes, Yi Zhu, Tamara Tchkonia, James L Kirkland

Abstract

Background: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.

Methods: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m2; eGFR:27·0 ± 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed.

Findings: D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12.

Interpretation: "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.

Keywords: Cellular senescence; Dasatinib; Diabetic kidney disease; Quercetin; Senescence-associated secretory phenotype; Senolytics.

Conflict of interest statement

J.L.K., T.T., Y.Z., and N.K.L. have a financial interest related to this research. Patents on senolytic drugs are held by Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. No conflicts of interest, financial or otherwise, are declared by the other authors.

Copyright © 2019. Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
D + Q decreases human adipose tissue senescent cells. (a). D + Q significantly reduced (p = 0·001) abdominal subcutaneous adipose tissue p16INK4A+ cells. Raw values were reduced by 35% in sections of adipose tissue biopsied at Day 14 (11 days after the last dose of a 3-day course of the senolytics) vs. at baseline (Day 0). At Day 0, there were 3·18 ± 0·64 p16INK4A+ cells/100 adipocytes (means ± SEM in 30 fields [400 × 300 μm] at 40× magnification). Means, standard errors, and standard deviations are shown in these “box and whisker” plots. The y axis shows p16INK4A+ cells in the 2 biopsies from each subject at Days 0 and 14 as % of each other (Arbitrary Units). N = 9 subjects; Welch's unpaired 2-tailed t-test for unequal variances. Representative images at Days 0 and 14 are shown. (b). D + Q significantly reduced (p = 0·009) adipose tissue p21CIP1+ cells. Raw values were decreased 17% by 11 days after completing D + Q treatment. At baseline (Day 0), there were 3·82 ± 0·65 p21CIP1+ cells/100 adipocytes (N = 9 subjects; means ± SEM). Representative images are shown. (c). D + Q significantly reduced (p = 0·005) adipose tissue SA-βgal-expressing cells. Raw values were decreased by 62% by 11 days after completing D + Q treatment. At baseline (Day 0), there were 8·76 ± 2·51 SAβgal+ cells/100 nuclei (N = 9 subjects; mean ± SEM). Representative images are shown. Scale bars = 100 μm. Exact p values are indicated. Colours indicate each individual's values on Days 0 and 14.
Fig. 2
Fig. 2
D + Q decreases human adipose tissue macrophages and crown-like structures. (a). D + Q significantly reduced (p = 0·0001) adipose tissue CD68+ macrophages relative to adipocytes. Raw numbers were decreased 28% by 11 days after completing D + Q treatment. At baseline, there were 8·4 ± 0·58 CD68+ macrophages/100 adipocytes (N = 9 subjects; mean ± SEM). Representative images at Days 0 and 14 are shown. (b). D + Q significantly reduced (p = 0·001) adipose tissue crown-like structures. Raw values were decreased by 11 days after D + Q treatment. At baseline (Day 0), there were 0·27 ± 0·05 CD68+ crown-like structures/100 adipocytes (N = 9 subjects; mean ± SEM). Representative images are shown. Scale bars = 100 μm. Exact p values are indicated. Colours indicate each individual's values on Days 0 and 14.
Fig. 3
Fig. 3
Increases in adipocyte progenitor cell density over time are enhanced following administration of D + Q, consistent with removal of cells with limited replicative potential (senescent and pre-senescent cells). Cell density/time was assayed by tetrazolium uptake in adipocyte progenitors isolated from adipose biopsies acquired before (Day 0) and 14 days after the first dose of the 3-day course of D + Q (Day 14) and cultured in parallel for 3 passages. Increases in cell density/time in adipocyte progenitors isolated after senolytic treatment were 8% greater than in adipocyte progenitors isolated before treatment (N = 11 subjects; Table 1). Exact p value is indicated. Colours indicate each individual's values on Days 0 and 14.
Fig. 4
Fig. 4
D + Q decreases human epidermal senescent cells. (a). D + Q significantly reduced (p = 0·026) human epidermal basal layer p16INK4A+ cells. Raw values were decreased 20% by 11 days after completing D + Q treatment. At baseline (Day 0), there were 1·95 ± 0·63 p16INK4A+ cells/mm of epidermis (N = 9 subjects; mean ± SEM). Representative images at Days 0 and 14 are shown. (b). D + Q significantly reduced (p = 0·016) human epidermal basal layer p21CIP1+ cells. Raw values were decreased 31% by 11 days after completing D + Q treatment. At baseline (Day 0), there were 1·71 ± 0·31 p21CIP1+ cells/mm of epidermis (mean ± SEM). Representative images are shown. (c). D + Q did not substantially change (p = .803) antigen-presenting CD1a+ epidermal Langerhans immune cells. At baseline (Day 0), there were 14·55 ± 2·16 CD1a+ cells/mm of epidermis (mean ± SEM; N = 9). Scale bars = 100 μm. Exact p values are indicated. Colours indicate each individual's values on Days 0 and 14.
Fig. 5
Fig. 5
D + Q decreases plasma SASP factors. Plasma SASP factors were assayed at baseline (Day 0) and after treatment (Day 14). Key SASP factors that were significantly decreased (p < 0·05) after treatment are shown. Colours indicate each individual's values on Days 0 and 14.

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